Gliomas are the most common brain tumors, and, in particular, grade IV glioma, also named glioblastoma multiforme (GBM), represents the most severe type. This highly aggressive tumor develops either de novo (primary GBM) or as consequence of the malignant progression from low-grade glioma (secondary GBM). In both cases, due to the intrinsic characteristic of this tumor, prognosis is poor and the median survival when radiotherapy and chemotherapy are combined is 14.6 months (12.).
Glioblastoma multiforme is a highly heterogeneous tumor, which shows clear cellular and tissue dissimilarities, displaying a strong hemorrhagic component and wide areas of necrosis, which, at the microscopic level, coincide with the presence of massive microvascular proliferation and pseudopalisading patterns (9.).
Most importantly, GBM is characterized by a diffuse tissue-distribution pattern, with extensive dissemination of the tumor cells within the brain that hinders complete surgical resection. Therefore, disease recurrence occurs in the majority of the patients. Moreover, GBM progression is also accompanied by extensive angiogenesis.
The need and importance is increasingly felt for the development of new markers, and for the identification of specific molecular targets for the development of a therapy for blocking the growth and diffusion of GBM and for its treatment.
In the last decade, several seminal studies have dealt with the identification and isolation of cancer stem cells (CSCs), which might be responsible for the initiation, maintenance and progression of different types of tumors. It has been suggested that the persistent growth of cancers, clonal diversification and evolution, tumor metastasis and recurrence after therapy may be the consequence of the maintenance by tumor cells of the proliferative potential of stem cells from which the tumor may have originated, which are called cancer stem cells. Transformed stem-like cells have been found in hematopoietic malignancies, breast cancer and stem-like neural progenitors also in human brain tissues.
The discovery that malignant brain tumors, or at least some of them, comprise cancer stem cells provides new opportunities at both the experimental and clinical level. In fact, even if the cancer stem cell hypotesis suggests that these cells constitute a minor cell pool within the overall tumor mass, this small pool, would be the true culprit responsible for establishing and expanding the tumor and perpetuating it following surgery.
Long-term proliferating cancer stem cells (CSCs) have been studied in GBM (GBM-CSCs), which possess both the full complement of neural stem cell functional characteristics (13.) and the ability to produce tumors which closely resemble the main histological, cytological and architectural features of the human GBM pathology (5.).
Due to their ability to generate true phenocopies of the human disease over time, these GBM-CSCs represent one of the most suitable models for studying GBM physiology in vitro and in vivo and might enable the discovery of genes/pathways directly involved in the regulation of the invasive and angiogenic behavior of the GBM itself. Molecular markers that either are found specifically on tumor cells or are highly over-expressed on malignant cells and nearly absent or downregulated on normal cells are attractive therapeutic targets for approaches such as targeted drug delivery. The Eph receptors comprise the largest family of tyrosine kinases encoded in the human genome and play important roles in development and disease receiving an external stimulus and responding by transmitting a signal to the inside of the cell, starting numerous processes that are vital for the maintenance of organism function. They can be distinguished from other RTKs in that they all recognize ligands, knows as ephrins, which are anchored to the membrane of apposing cells. Ligand binding typically triggers tyrosine phosphorylation of Eph receptors. (4.).
It is therefore object of the present disclosure the development of novel and more specific therapeutic strategies for brain cancers, in particular to identify an inhibitor of the growth and proliferation of glioblastoma.